BH3-only proteins are dispensable for apoptosis induced by pharmacological inhibition of both MCL-1 and BCL-X
Apoptosis
/ drug effects
Cell Death
/ drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Humans
Mitochondrial Membrane Transport Proteins
/ metabolism
Myeloid Cell Leukemia Sequence 1 Protein
/ antagonists & inhibitors
Pyrimidines
/ pharmacology
Structure-Activity Relationship
Thiophenes
/ pharmacology
bcl-X Protein
/ antagonists & inhibitors
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
14
05
2018
accepted:
24
07
2018
revised:
23
07
2018
pubmed:
7
9
2018
medline:
2
10
2020
entrez:
7
9
2018
Statut:
ppublish
Résumé
The impressive selectivity and efficacy of BH3 mimetics for treating cancer has largely been limited to BCL-2 dependent hematological malignancies. Most solid tumors depend on other anti-apoptotic proteins, including MCL-1, for survival. The recent description of S63845 as the first specific and potent MCL-1 inhibitor represents an important therapeutic advance, since MCL-1 is not targeted by the currently available BH3 mimetics, Navitoclax or Venetoclax, and is commonly associated with chemoresistance. In this study, we confirm a high binding affinity and selectivity of S63845 to induce apoptosis in MCL-1-dependent cancer cell lines. Furthermore, S63845 synergizes with other BH3 mimetics to induce apoptosis in cell lines derived from both hematological and solid tumors. Although the anti-apoptotic BCL-2 family members in these cell lines interact with a spectrum of pro-apoptotic BH3-only proteins to regulate apoptosis, these interactions alone do not explain the relative sensitivities of these cell lines to BH3 mimetic-induced apoptosis. These findings necessitated further investigation into the requirement of BH3-only proteins in BH3 mimetic-mediated apoptosis. Concurrent inhibition of BCL-X
Identifiants
pubmed: 30185825
doi: 10.1038/s41418-018-0183-7
pii: 10.1038/s41418-018-0183-7
pmc: PMC6748112
doi:
Substances chimiques
BCL2L1 protein, human
0
MCL1 protein, human
0
Mitochondrial Membrane Transport Proteins
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Pyrimidines
0
RTL10 protein, human
0
S63845
0
Thiophenes
0
bcl-X Protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1037-1047Subventions
Organisme : Medical Research Council
ID : G120/1030
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R01 GM118437
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA205496
Pays : United States
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